Oximino ethers of phenylacetophenones



United States Patent 3,247,243 GXIMINO ETHERS OF PHENYLACETO- PHEN ONES Frank J. Villani, West Caldwell, N .J assignor to Schering Elorporation, Bloomfield, N.J., a corporation of New uersey No Drawing. Filed June 28, 1963, Ser. No. 291,259

3 Claims. (Cl. 260501) This invention relates to compositions of matter identifinble as oximino derivatives of a-phenylacetophenones and to processes for mak ng and using such compositions.

The invention sought to be patented in its composition aspect is described as residing in the concept of a chemical compound having the molecular structure of an aphenylacetophenone oxime in which the hydrogen atom of the oximino portion has been replaced by the substituent -QT, with Q being lower alkylene and T is a di-lower alkyl amino group or its hereinafter disclosed equivalent.

The invention sought to be patented in its process aspect is described as residing in the concept of preparing the tangible embodiments of the composition aspect by the reaction of an a-phenylacetophenone with a substi tuted hydroxylarnine, that is, one of the formula H NOQT (Where Q and T are as above defined) or in the alternative reacting an e-phenylace-tophenone oxime with an allqrating agent such as of the formula ClQT (where Q and T are as above defined).

The tangible embodiments of the composition aspect of the invention possess the inherent general physical properties of being substantially insoluble in water, soluble in aqueous acid and soluble in most common organic solvents. These compositions are generally high boiling liquids purifiable by vacuum distillation.

The tangible embodiments of the invention possess the inherent applied use characteristics of exerting an antifertility effect as evidenced by pharmacological evaluation in female rats subjected to standard mating tests. In addition, they exert an anticholesterimic effect, as evidenced by pharmacological evaluation.

Each of the aromatic rings of the a-phenylacetophenone oximino embodiment may contain substituents in one or more of the available positions, said substituents being those normally associated with such structures as halogen, hydroxyl, lower alkoxy, lower alkanoyloxy and lower alkyl. A desirable structure is that containing methoxy in at least one of the two available para positions and preferably in both positions. The zit-carbon atom of the a-phenylacetopnenone preferably contains a lower alkyl group with ethyl being the substituent of choice. All of these structures are contemplated as essential equivalents although they indeed may differ somewhat in the degree of activity elicited.

As used herein, the term lower alkylene means a bivalent hydrocarbon radical including straight and branched chain radicals among which are ethylene, 1,3- propylene, 1,2-propylene, 1,4-butylene, 1,2-butylene, 1,3- butylene, 1,5-pentylene, 2-ethyl-1,3-propylene and the like. Further, as used herein, the term di-lower alkylamino means an amino group substituted by lower alkyl radicals including the straight and branched chain radicals among which are methyl, ethyl, propyl and the like as well as the obvious cyclic equivalents of such as, for exice ample, pyrrolidine, piperidino, morpholino and piperaz In one of the process aspects, the tangible embodiments of this invention are prepared by reacting an ocphenylacetophenone with a di-lower alkyl amino lower alkyl hydroxylamine (referred to above as H NOQT). The substituted hydroxylamine reagent is preferably used in the form of its acid addition salt, such as in the form of a dihydrochloride. The substituted hydroxylamine reagent can be prepared by methods well known in the art. Exemplary of such known methods is the following general procedure which involves treating an acetone oxime (I) with a dialkylaminoalkylhalide (dimethylaminoethylchloride, (II), in the presence of a base such. as sodamide or sodium ethoxide. The dimethylaminoethyloximino derivative (III) is isolated by distillation upon treatment with dilute acid, the oxime (III) is split regenerating acetone and the substituted hydroxylarnine (IV) which is used in preparing a tangible embodiment of the instant invention.

base (CH3) 2C=NOH C10 H2O HzN (0 H 2 (CH3)2C=NO CHZCH2N(CH3) 2 (III) l dilute HCl HZNOOHQGHZMCHQMHQ The other amino alkylhydronylamines discussed above in conjunction with the definitions of Q and T are the full equivalents of dimethylaminoethoxyarnine, IV above, and can be prepared in a manner similar to that described for preparing dirnethyl'aminoethoxyamine.

The substituted hydroxylarnine reagent (IV) is reacted with an a-phenylacetophenone (V) preferably in a polar organic solvent in the presence of a tertiary base. It has been found that ethanol-pyridine affords a satisfactory solvent. Heating the mixture at reflux results in oximation of the a-phenylacetophenone (V) resulting in the formation of a tangible embodiment of this invention (VI). This latter salt is transformed into its base form (VII) by usual procedures involving use of a base and extracting solvents such as chloroform. The compounds such as VII are purified in the first instance by distillation. By way of illustration, the following reaction scheme is presented showing the transformation of aethyl-u-p-methoxyphenyl-4-methoxyacetophenone:

0 C Ha I pyridine HC-C 2H HQNO CHzC HzN (CH .21101 I ethanol 0:0 (IV) A l 0 C H V) I 2. extract C=NO CHzC H2N(CH3) 2 l OGHs An alternate method for preparing the tangible embodiment of this invention is shown in the following general procedure which involves treating an u-phenylacetophenone oxime (VIII) With a di-lower alkylaminoalkylhalide (H) in the presence of a basic agent followed by work-up in a usual manner. There is thus produced the oxirnino derivative, VII:

(VIII) (v11 This latter alky-lation reaction is generally effected in a refluxing solvent and worked up by neutralization and extraction. The base is present to'take up the acid formed during the reaction; however, as will be apparent to one skilled in the art, the reactions may be etfected with a base which may be added sequentially to neutralize the acid addition salt of the reaction product.

The following preparations and examples are illustrative of the preferred modes for carrying out the invention:

PREPARATION OF STARTING MATERIALS Preparation A.Oxime Reagent DIMETHYLAMINOETHOXYAMINE DIHYDROCHLORIDE Admix 73 g. acetone-oxime, 1 mole of dimethylaminoethylchloride hydrochloride, 427 g. of anhydrous potassium carbonate and 1.5 1. benzene. Stir and reflux overnight. Cool, filter, and wash precipitate with hot benzene. Combine filtrates, concentrate to a residue and distill in vacuo to obtain the dirnethylaminoethyl ether of acetoneoxime (B.P. 85-88/50 mm.).

Admix 100 g. of acetone-oxirne of the above and 1 liter of aqueous hydrochloric acid. Stir on a steam bath for 15 hours. Concentrate to a residue in vacuo.

Recrystallize the residue from methanol ether solvent obtaining dimethylaminoethoxyarnine dihydrochloride, M.P. 181182.5 C.

By substituting other equivalent tertiary-aminoalkylchloride hydrochlorides for dimethylaminoethylchloride hydrochloride in the above preparation, the correspond-- ing t-aminoalkoxyamine hydrochlorides are obtainable. Accordingly, there may be prepared by this method ox-ime reagents exemplified by the following alkoxyamines (it is understood that these reagents are prepared as above and are obtained in the form of their (ii-hydrochloride salts): dimethylaminopropoxyamine, dimethy-laminobutoxyamine, diethylaminoethoxyamine, diethylaminopropoxyamine, diethylaminoisopropoxyamine, diethylaminopentoxyamine pyrrolidinoethoxyamine, pyrrolidinopropoxyamine, piperidinoethoxyamine, piperidinopropoxyamine, morpholinoethoxyamine, morpholinobutoxyamine, piperazinoethoxyamine, N-l-methyl-N 4 piperazinoethoxyamine and N-l-(hydroxyethyD-N-4-propoxyamine.

Starting materials such as the ot-phenylacetophenones and oxsimes thereof are for the most part known in the art or are preparable by methods described in the art.

Example 1.--Dimethylaniinoetlzyl ether 0 ct-ethyl-a-(pmethoxy-phenyl)-4-meflz0xyacet0phen0ne oxime from the oxime N-O-CHzC IIzN (C H3) 2 Prepare a solution of sodium ethoxide from 2 g. of sodium and ml. of ethanol. Add .9 'g. of cat-@IllYl-cc-(P- methoxyphenyl)-4-methoxyacetophenone oxirne. Stir for 10 minutes and then add 6 g. of dimethylaminoethylohloride hydrochloride. Stir and reflux 12-14 hours. Remove solvent by evaporating in vacuo. Dissolve residue in water (which should test alkaline) and extract with ether. Extract the ether solutions with dilute hydrochloric acid. Neutralize the acid solution with excess sodium hydroxide and extract the slightly alkaline mixture with chloroform. Distill in vacuo obtaining the product of this example, B.P. 2l922l/2 mm. (11 about 1.5659).

By substituting different phenylacetophenones and/or ditferent amino alkylating agents in the foregoing procedure, products equivalent to the foregoing are obtained. Listed below in tabular form are representations of the starting oxime; amino alkylating agent. The product obtained from such reactants is analogous to the ether of this example differing in structure only as the reactants themselves diifer structurally from the reactants described herein:

6 Example 2.-Dimethylaminoethyl ether of a-etIzyl-a-(ption from solvents such as alcoholic ether. Representamethoxyphenyl)-4-metlzoxyacetophen0ne oxime from tive pharmaceutically acceptable acid addition salts are the acetophenone formed with inorganic acids such as hydrochloric and C|ZH5 (32115 cao m 1 H.NOCH.CH.N GH. .2HC1 OH.O C O@H. H 0 a N NOCH2CH2N( a)2 Dissolve 28.4 g. of a-ethyl-a-(p-methoxyphenyl)-4- organic acids such as maleic, succinic, salicylic and the methoxyacetophenone in a solution of 100 ml. of pyridine like. Salt formation generally renders the oxirnino ether and 100 ml. ethanol. Add 20 g. of dimethylaminoeth- Water soluble and aiiords a means for handling the ether oxyarnine dihydrochloride. Stir and reflux for six hours. in the form of a crystalline solid. Remove solvents in vacuo, dissolve residue '11 Water and It is known to chemists that the oximino ethers of this render the aqueous mixture alkaline with sodium biinvention may exist in either one or both of two geocarbonate solution. Extract the mixture with ether, and metric configurations; one being syn and the other anti. then extract the ether solution with dilute hydrogen Either or both structures are contemplated as with the chloride. Render the acid solution alkaline with amscope of this invention.

monium chloride and extract With chloroform. Distill Iclaim:

as in Example I. 1. A compound selected from the group consisting of By substituting equivalent quantities of different acetoa free base and its pharmaceutically acceptable acid ad phenones and/or different oximating agents in the foredition salts, the free base having the structural formula:

going procedure, equivalent products are obtained. Rep- @330 lower alkyl 00m resentations of various reactants are shown in the following tabulation. The products obtained therefrom are (|3*C analogous to the ether of this example: H

N-O-l0wer alkylene-N (lower alkylh 2. The compound having the structural formula:

Acetophenone C 2H5 I 1 C H H chloride) NOOHwBtNwHQf It 0 3. A pharmaceutically acceptable acid addition salt of the compound of claim 2. R1 R2 3 References Cited by the Examiner 5 5%; Egg]; g g: UNITED STATES PATENTS 5 gI Z P432117 g gigggfigg 1,921,424 8/ 1933 Nabenhauer 260-566 p-Ogga 1-88%; 1605 t g rlietgylam noetlr 40 2,712,031 6/1955 Huflman 260-566 XR 8 3 g fg g j' J ie 5 3 5 3333 1; 2,832,804 4/1958 Richter et al. 260566 XR 0011; -gggs r-rethoxy phenyl g metl amrnoegg- 2,888,464 5/ 1959 Shapiro et a1. H 5 i dia r iti giifigfiimg. 2,921,080 1/1960 Archer et al. 260566 XR 5 00a; 3 0C112 Gin? fiiiisiit- 3,060,177 10/1962 Druey et a1. 260566 X p-OCHs 1 2 5 morpholmoeth' 4 FOREIGN PATENTS 301,956 12/ 1928 Great Britain.

It will be apparent to one skilled in the art that acid QTHER REFERENCES addition salts of the oximino ethers may be prepared by any of the conventional methods such as dissolving the f et Helv' Chlm' Acta 1381" basic ether in an organic solvent in which the salt is not Sie et a1 Ch 1 22 soluble and adding thereto an acid containing the desired g g. v0 1 954 (1957) anion. The precipitated salt is purified by recrystalliza- CHARLES B, PARKER, P ima y E min 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A FREE BASE AND IS PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS, THE FREE BASE HAVING THE STRUCTURAL FORMULA: 